Human immunodeficiency virus (HIV) rapidly penetrates the central nervous system (CNS) and can lead to varying levels of neuronal loss and neurological impairments including AIDS dementia. Because interactions of the virus with the CNS prior to the development of AIDS probably set the stage for subsequent disease progression, early intervention is likely to be important for effective treatment of the neurological and behavioral complications of HIV infection. Microglia and macrophages are thought to play a key role in the penetration of the virus into the nervous system and subsequent pathogenesis. However, our understanding of the interactions of the virus with brain microglia and macrophages is still quite limited. Specifically, little is know about the relative role of microglia and macrophages in pathogenesis, the stimuli that provoke the activation of these cells and release of putative toxins, and the mechanisms that lead to neuronal dysfunction. Using feline immunodeficiency virus (FIV) we have developed a model of viral infection and pathogenesis that may help to explain how each cell might contribute to evolving pathogenesis. This model suggests that the macrophage population within the choroid plexus could maintain a virus reservoir capable of infecting T-cells locally and perhaps contribute to the trafficking of macrophages and secretion of neurotoxins. Using primary cultures of brain microglia, choroid plexus macrophages and neurons, we will determine the viral and non-viral stimuli that induce microglial and macrophage activation and secretion of toxins. Microglial/macrophage activation will be assessed by evaluating increases in intracellular calcium in vitro, production of cytokine and chemokine mRNA and the accumulation of substances toxic to cortical cat neurons in primary culture. In addition, we will pharmacologically characterize the actions of the secreted toxins on neurons that lead to the destabilization of intracellular calcium. Microglia, macrophages or T-cells infected in vitro will then be infused into the brain ventricles to generate an in vivo model of central nervous system pathogenesis. These studies will clarify the role of microglia, macrophages and T-cells in the inflammatory response that develops in the brain following lentivirus infection and help to generate an animal model of macrophage-induced toxicity that can be used for identification and evaluation of improved strategies for early therapeutic intervention.